Penciclovir for the treatment of post therapeutic neuralgia

ABSTRACT

A method for the treatment of PHN in mammals, including humans, which method comprises administering an effective amount of a compound of formula (A), or a pharmaceutically acceptable salt thereof. ##STR1##

This application is a 371 of PCT/GB94/02156 filed Oct. 4, 1994.

FIELD OF THE INVENTION

This invention relates to treatment of post-herpetic neuralgia, and tothe use of compounds in the preparation of a medicament for use in thetreatment of such conditions.

When used herein, `treatment` includes prophylaxis as appropriate.

BACKGROUND OF THE INVENTION

EP-A-141927 (Beecham Group p.l.c.) discloses penciclovir, the compoundof formula (A): ##STR2## and salts, phosphate esters and acylderivatives thereof, as antiviral agents. The sodium salt hydrate ofpenciclovir is disclosed in EP-A-216459 (Beecham Group p.l.c.).Penciclovir and its antiviral activity is also disclosed in AbstractP.V11-5 p. 193 of `Abstracts of 14th Int. Congress of Microbiology`,Manchester, England 7-13 Sep. 1986 (Boyd et. al.).

Orally active bioprecursors of the compound of formula (A) are offormula (B): ##STR3## and salts and derivatives thereof as defined underformula (A); wherein X is C₁₋₆ alkoxy, NH₂ or hydrogen. The compounds offormula (B) wherein X is C₁₋₆ alkoxy or NH₂ are disclosed in EP-A-141927and the compounds of formula (B) wherein X is hydrogen, disclosed inEP-A-182024 (Beecham Group p.l.c.) are preferred prodrugs. Aparticularly preferred example of a compound of formula (B) is thatwherein X is hydrogen and wherein the two OH groups are in the form ofthe acetyl derivative, described in Example 2 of EP-A-1 82024,hereinafter referred to as famciclovir.

The compounds of formulae (A) and (B) and salts and derivatives thereofhave been described as useful in the treatment of infections caused byherpesviruses, such as herpes simplex type 1, herpes simplex type 2,varicella-zoster and Epstein-Barr viruses.

Post-herpetic neuralgia (PHN) is by far the most common complication ofherpes zoster infection and is one of the most intractable paindisorders (Strommen et al, Pharmacotherapy. 1988;8:52-68). Patients whodevelop PHN suffer from a debilitating and often intractable pain whichcan persist for months or even years. Although rare in patients under 50years of age, the frequency of PHN rises steeply with increasing age.

There is currently no proven therapy for preventing PHN. The pain is dueto injury of the nervous system and therefore seldom responds toanalgesia used to treat pain associated with tissue damage. Hence, thereis a need for therapy which alleviates or shortens the duration ofpost-herpetic neuralgia.

SUMMARY OF THE INVENTION

It has now been discovered that the above compounds are particularlyeffective in reducing the duration of PHN when given to the patientduring the acute infection.

Accordingly, the present invention provides a method of treatment of PHNin humans, which method comprises the administration to the human inneed of such treatment, an effective amount of a compound of formula(A): ##STR4## or a bioprecursor, or a pharmaceutically acceptable salt,phosphate ester and/or acyl derivative of either of the foregoing.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a Kaplan-Meier Plot of Time to Loss of PostherpeticNeuralgia (PHN) in a Patient Population in which famciclovir dosessignificantly reduce the duration of PHN.

FIG. 2 shows a Kaplan-Meier Plot of Time to Loss of PostherpeticNeuralgia (PHN) in a Patient Population over >50 years of age in whichfamciclovir resolved PHN 2.6 times faster than in placebo treatedpatients.

DETAILED DESCRIPTION OF THE INVENTION

The term `acyl derivative` is used herein to include any derivative ofthe compounds of formula (A) in which one or more acyl groups arepresent. Such derivatives are included as bioprecursors of the compoundsof formula (A) in addition to those derivatives which are per sebiologically active.

The compound of formula (A) may be in one of the forms disclosed inEP-A-216459 (Beecham Group p.l.c.).

Examples of bioprecursors, pharmaceutically acceptable salts andderivatives are as described in the aforementioned European Patentreferences, the subject matter of which are incorporated herein byreference.

A particular compound of formula (B) of interest is9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-aminopurine, known asfamciclovir (FCV), the well-absorbed oral form of penciclovir (PCV).

The compound of formula (A), bioprecursors, salts and derivatives may beprepared as described in the aforementioned European Patent references.

The compound, in particular, famciclovir, may be administered by theoral route to humans and may be compounded in the form of syrup, tabletsor capsule. When in the form of a tablet, any pharmaceutical carriersuitable for formulating such solid compositions may be used, forexample magnesium stearate, starch, lactose, glucose, rice, flour andchalk. The compound may also be in the form of an ingestible capsule,for example of gelatin, to contain the compound, or in the form of asyrup, a solution or a suspension. Suitable liquid pharmaceuticalcarriers include ethyl alcohol, glycerine, saline and water to whichflavouring or colouring agents may be added to form syrups. Sustainedrelease formulations, for example tablets containing an enteric coating,are also envisaged.

For parenteral administration, fluid unit dose forms are preparedcontaining the compound and a sterile vehicle. The compound depending onthe vehicle and the concentration, can be either suspended or dissolved.Parenteral solutions are normally prepared by dissolving the compound ina vehicle and filter sterilising before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, preservatives and buffering agents are also dissolved inthe vehicle. To enhance the stability, the composition can be frozenafter filling into the vial and the water removed under vacuum.

Parenteral suspensions are prepared in substantially the same mannerexcept that the compound is suspended in the vehicle instead of beingdissolved and sterilised by exposure to ethylene oxide before suspendingin the sterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound of the invention.

Preferred parenteral formulations include aqueous formulations usingsterile water or normal saline, at a pH of around 7.4 or greater, inparticular, containing penciclovir sodium salt hydrate.

As is common practice, the compositions will usually be accompanied bywritten or printed directions for use in the medical treatmentconcerned.

An amount effective to treat the virus infection depends on the natureand severity of the infection and the weight of the mammal.

A suitable dosage unit might contain from 50 mg to 1 g of activeingredient, for example 100 to 500 mg. Such doses may be administered 1to 4 times a day or more usually 2 or 3 times a day. The effective doseof compound will, in general, be in the range of from 0.2 to 40 mg perkilogram of body weight per day or, more usually, 10 to 20 mg/kg per dayin the case of famciclovir, the dosage unit would be 250 mg, 500 mg or750 mg, preferably 250 mg or 500 mg.

The treatment is preferably carried out as soon as possible aftersymptoms appear usually within 72 hours, preferably within 48 hours ofrash onset.

The treatment period is usually 7 days.

The treatment is particularly effective in the case of patients ofgreater than 50 years of age, and efficacy would be expected to bedemonstrated further in patients greater than 60 years of age,especially patients of greater than 70 years of age.

The present invention also provides the use of a compound of formula (A)or a bioprecursor, or a pharmaceutically acceptable salt, phosphateester and/or acyl derivative of either of the foregoing, in thepreparation of a medicament for use in the treatment of PHN. Suchtreatment may be carried out in the manner as hereinbefore described.

The present invention further provides a pharmaceutical composition foruse in the treatment of PHN, which comprises an effective amount of acompound of formula (A) or a bioprecursor, or a pharmaceuticallyacceptable salt, phosphate ester and/or acyl derivative of either of theforegoing, and a pharmaceutically acceptable carrier. Such compositionsmay be prepared in the manner as hereinafter described.

The compound of formula (A) and its prodrugs show a synergisticantiviral effect in conjunction with interferons; and treatment usingcombination products comprising these two components for sequential orconcomitant administration, by the same or different routes, aretherefore within the ambit of the present invention. Such products aredescribed in EP-A-271270 (Beecham Group p.l.c.).

The following clinical data and paper for publication, entitled`Famciclovir for the treatment of Acute Disease and PostherpeticNeuralgia` illustrate the invention.(ref.--Tyring et al Abstract 1540 ofthe 32nd Interscience Conference on Antimicrobial Agents andChemotherapy. New Orleans. American Society of Microbiology, 1993.)

Clinical Data

A prospective, randomized, double-blind study was conducted to compareFCV dosed at 500 mg and 750 mg tid for 7 days with placebo in thetreatment of uncomplicated herpes zoster. 419 immunocompetent patients,aged ≧18 years whose zoster rash had been present for ≦72 hours wereenrolled. Patients were assessed for lesion condition and painpre-therapy, daily during week 1, daily until full crusting during week2 and then weekly until all crust had been lost. Both FCV doses wereequally effective and significantly reduced the duration of VZV recoveryfrom zoster lesions and the time to healing of zoster lesions comparedwith the placebo-treated group. In addition, a statistically significantdecrease in the duration of acute phase pain was detected forfamciclovir-treated patients presenting with severe rash when comparedwith placebo. The effect of famciclovir on PHN (defined as pain at orafter healing) was evaluated by assessing pain at 5 monthly visits afterhealing. The duration of PHN for all age groups was significantlyreduced from 128 days to 62 and 55 days following treatment with FCV 500mg and 750 mg, respectively. There were no significant differences inthe safety profiles between famciclovir and placebo. In conclusion, thisstudy demonstrates that famciclovir dosed tid is an effective and welltolerated treatment for patients with acute herpes zoster infection,significantly decreasing the time to cutaneous lesion resolution and theduration of PHN.

The median times to loss of pain following healing in the above studywere compared with those seen in a second study (not placebo controlled)for all patients and in patients ≧50 years of age, to confirm that thespeed of pain resolutions were of the same order.

    ______________________________________                      FCV     FCV     FCV    Study    Group    250 mg  500 mg  750 mg                                            Placebo    ______________________________________    first    All      56      51      38    second   All              63      61    119    first    ≧50 yrs                      56      55      43    second   ≧50 yrs   63      63    163    ______________________________________

These findings therefore further support the conclusions from theplacebo-controlled study that famciclovir provides a significantclinical benefit in shortening the duration of post-herpetic neuralgia.

Famciclovir for the Treatment of Acute Herpes Zoster Effects on AcuteDisease and Postherpetic Neuralgia

Authors: Stephen Tyring, MD, PhD,* Rick A. Barbarash, PharmD,† James E.Nahlik, MD,‡ Anthony Cunningham, MBBS, MD,§ John Marley, MD,∥ MadaleneHeng, MD,¶ Terry Jones, MD,** Ted Rea, MD,** Ron Boon, B.Sc.(Hons).,C.Bioi., M.l. Biol., †† Robin Saltzman, MD,†† and The CollaborativeFamciclovir Herpes Zoster Study Group.

Authors' Affiliations: *University of Texas Medical Branch, Galveston,Tex. and St. John Hospital, Nassau Bay, Tex.; †St Louis University, StLouis, Mo.; ‡Deaconess Family Medicine, St Louis, Mo.; §WestmeadHospital, Westmead, Australia; ∥University of Adelaide, Adelaide,Australia; ¶VA Medical Center, Sepulveda, Calif.; **Volunteers inPharmaceutical Research, Bryan Tex.; ††SmithKline BeechamPharmaceuticals, Brentford, Middlesex, United Kingdom and Philadelphia,Pa.

Corresponding author/Address for reprint requests:

Stephen Tyring, MD, PhD

University of Texas Medical Branch

Center for Clinical Studies

2060 Space Park Drive, Suite 200

Nassau Bay, Tex. 77055

Phone: (713) 333-2288

Fax: (713) 333-2338

Supported by a grant from SmithKline Beecham Pharmaceuticals.

Short Title: Famciclovir: Effects on Acute Zoster and PHN

Number of Words: 3,692

Abstract

Objective: To document the effects of treatment with famciclovir on boththe acute signs and symptoms of herpes zoster and postherpeticneuralgia.

Design: A randomized, double-blind, placebo-controlled, multicentertrial.

Setting: Thirty-six centers in the United States, Canada, and Australia.

Patients: Adults (419) with uncomplicated herpes zoster.

Intervention: Patients were randomized within 72 hours after rash onsetto receive famciclovir 500 mg, famciclovir 750 mg, or placebo threetimes daily for seven days.

Measurements: Lesions were assessed daily for up to 14 days until fullcrusting and then weekly until healing. Viral cultures were obtaineddaily while vesicles were present. Pain was assessed at each visit atwhich lesion assessments were made and then monthly for five monthsfollowing healing. Safety was assessed for the duration of the study.

Results. Famciclovir was well tolerated, with a safety profilecomparable with that of placebo. Famciclovir significantly acceleratedlesion healing and reduced the duration of viral shedding. Mostimportantly, patients treated with famciclovir had a significantly morerapid resolution of postherpetic neuralgia (˜2-fold faster) whencompared with placebo recipients, resulting in about a two monthreduction in the median duration of postherpetic neuralgia.

Conclusions. Oral famciclovir 500 mg or 750 mg given three times dailyfor seven days is an effective and well tolerated treatment for herpeszoster and significantly decreases the duration of the most debilitatingcomplication, postherpetic neuralgia.

Introduction

Herpes zoster (shingles) occurs in 20% of the population and theincidence of the disease increases (three to four times) in the elderly(1). The characteristic zoster rash is often accompanied by significantpain, dysesthesias, and skin hypersensitivity. The unmet challenge inthe management of patients with acute zoster is the amelioration ofchronic pain. In many patients pain is lost once the affected area ofskin returns to normal. However, some patients continue to experiencepain long after healing and this is commonly referred to as postherpeticneuralgia. Postherpetic neuralgia is by far the most common complicationof herpes zoster infection and is one of the most intractable paindisorders (2,3). The incidence of postherpetic neuralgia rises sharplywith increasing age (4,5); nearly half of patients over 60 years of agewill suffer from this complication (2,5). Postherpetic neuralgia inolder patients is also more severe and persists longer than in youngerpatients (3), and is clearly the most distressing component of thedisease process for both the patient and the physician. Although formany years acyclovir has been the only oral antiviral agent approved forthe treatment of patients with acute herpes zoster infections, whetherit has an effect on postherpetic neuralgia remains controversial (6-10).

Famciclovir is the well absorbed (77% bioavailable) (11) oral form ofpenciclovir, a new antiviral agent with activity againstvaricella-zoster virus (VZV), herpes simplex virus (HSV) types 1 and 2,and Epstein-Barr virus (12-15). The in vitro potency of both penciclovirand acyclovir are dependent on the host cell and assay method used, butare generally comparable (14-16). The 50% plaque inhibitoryconcentrations (IC₅₀) in VZV-infected human lung fibroblasts were4.0±1.5 mcg/mL and 4.0±1.1 mcg/mL for penciclovir and acyclovir,respectively (14). A potentially clinically important characteristic ofpenciclovir-triphosphate (PCV-TP) is that it persists in virus-infectedhost cells longer than acyclovir-triphosphate (ACV-TP) (17). ForVZV-infected cells, the intracellular half-life of PCV-TP is 9.1 hours,in contrast to 0.8 hours for ACV-TP (17,18). Thus, PCV-TP has thepotential to continue to inhibit viral replication even if serumconcentrations are below the inhibitory level. Consistent oralbioavailability linked to a favorable intracellular half-life of PCV-TPin VZV-infected cells suggested that famciclovir could offer clinicallyimportant advantages in the management of herpes zoster infections overcurrently available therapy: a reduced total daily dose and a reduceddosing frequency. Also, there was the expectation that more completecover of antiviral activity throughout the dosing period could lead toimproved clinical efficacy, especially with regard to postherpeticneuralgia. As a result, a study was designed to examine the effects offamciclovir on acute herpes zoster and postherpetic neuralgia.

METHODS Study Design

This study was a randomized, double-blind, placebo-controlled,multicenter trial to assess the efficacy and safety of famciclovir 500mg or 750 mg versus placebo, given three times daily for seven days inthe treatment of patients with uncomplicated acute herpes zosterinfection.

Patients ≧18 years of age with clinically diagnosed uncomplicated herpeszoster infection based on clinical judgment who gave written informedconsent were eligible for study entry. Exclusion criteria includedpatients with zoster rash that had been present for >72 hours;complications of herpes zoster (eg, ocular or visceral involvement,disseminated zoster); presence of crusts at enrollment; patients withother serious underlying disease (eg, immunocompromised and/orHIV-infected individuals); or pregnant or lactating females.

Patients were prohibited from receiving any concomitant antiviral orimmunomodifying therapy and any topical medication which would beapplied to zoster lesions during the course of the study.

Patient Assessments

Patients were instructed to return to the clinic for lesion and painevaluations each of the seven therapy days and every day for the nextseven days following therapy. Patients with lesions that were fullycrusted by day 7 were examined every other day of the week followingtherapy. After day 14, weekly visits were required of all patients untilall lesions had lost their crusts. Patients were assessed for thepresence of postherpetic neuralgia at monthly intervals followinghealing for an additional five months.

The number of papules, vesicles, ulcers, and crusts within the primarydermatome was recorded as none, mild (<25 lesions), moderate (25-50lesions), or severe (>50 lesions). A specimen for viral culture wastaken at baseline and daily thereafter while vesicles were present.Patients were asked to rate the intensity of their pain on a scale ofnone, mild, moderate, or severe.

Adverse events were assessed at each visit according to time of onset,duration, severity, and investigator defined relationship to studymedication. Blood samples were obtained for assessment of chemistry andhematology and urine samples were obtained for dipstick analysis priorto study medication initiation and at the end of therapy visit.

Statistical Analysis

Efficacy endpoints were analyzed by standard survival methods. Analysesemployed the Cox proportional-hazards regression model (19).Time-dependent covariates were modeled to evaluate the proportionalhazards assumption and a model including the main effects of treatmentwas employed to examine efficacy. Statistical conclusions were based onthe significance of estimated hazard ratios. These were constructed suchthat values larger than one indicated a faster rate of event occurrencein famciclovir-treated patients than placebo. Two comparisons were madefor each endpoint: famciclovir 500 mg versus placebo and famciclovir 750mg versus placebo. In addition, Kaplan-Meier estimates of the cumulativeproportion of patients achieving an event were employed to graphicallyillustrate the trial results. Proportion data were analyzed by means ofFishers exact test (2-tailed).

The primary efficacy variable was time to full crusting. Secondaryvariables included duration of viral shedding; time to loss of vesicles,ulcers, crusts, and acute pain; and duration of postherpetic neuralgia(ie, time to loss of pain after healing). Healing was defined as thefirst visit at which a patient had no papules, vesicles, ulcers, orcrusts, and did not develop them at any later visit. Similarly, time toloss of a parameter was the time to complete cessation of that parameterwith no further report at any later date. Duration of viral shedding wasmeasured as the number of days from first dose of study medication tothe last positive culture.

The pre-study enrollment objective was 300 patients (100 per group). Thesample provided 80% power to detect a significant difference fromplacebo, assuming a true hazard ratio of 1.5 and exponential time tofull crusting (or time to event). Data from both the intention-to-treat(patients receiving at least one dose of study medication) andefficacy-evaluable (patients in compliance with the protocol)populations were analyzed. As the results of both analyses weregenerally comparable, in the current report, data are presented for theintention-to-treat population, unless otherwise specified. Prospectivelydefined subgroups with respect to age, duration of rash at enrollment,and severity of rash at enrollment were also examined. The safetyanalysis included all patients who had received at least one dose ofstudy medication. Each analysis included all patients providinginformation for the respective endpoint. That is, for example, theanalysis for time to loss of crusts included all patients who presentedwith crusts during the study.

RESULTS Demographics

Characteristics of all randomized patients (n=419) are shown in Table 1,including gender, age, duration of rash, location of rash, severity ofrash, and severity of pain. Approximately half of the patients werefemale. Mean age was 50 years. Over half of the patients had severe rashat enrollment and more than 60% of the patients had moderate or severezoster pain at enrollment.

Dermatological Assessment

Famciclovir treatment significantly accelerated lesion healing comparedwith placebo, as demonstrated by shorter times to full crusting, loss ofvesicles, loss of ulcers and loss of crusts. In general, the analysesfor both the intention-to-treat and the efficacy-evaluable populationswere similar and are presented in Table 2.

As noted above, full crusting occurred at a faster rate in patients whoreceived famciclovir compared with those who received placebo. In theintention-to-treat and efficacy-evaluable analyses, the hazard ratiosindicate a 1.3-1.5-fold faster time to full crusting for both thefamciclovir 500 mg group (hazard ratio: intention-to-treat=1.3;efficacy-evaluable=1.5) and the famciclovir 750 mg group (hazard ratio:intention-to-treat=1.4; efficacy-evaluable=1.5). Statisticallysignificant differences were detected for the famciclovir 500 mgrecipients in the efficacy-evaluable analysis (p=0.0245) and for thefamciclovir 750 mg recipients in the intention-to-treat and efficacyevaluable analyses (p=0.0228 and 0.0162, respectively).

Virological Assessment

Famciclovir significantly reduced the duration of viral sheddingcompared with placebo (p=0.0001). At baseline, 58%, 67%, and 70% ofpatients in the famciclovir 500 mg, famciclovir 750 mg, and placebogroups, respectively, had positive cultures for VZV. The proportion ofpatients who had stopped shedding virus after one day of treatment wasapproximately 60% for the famciclovir groups, compared with only 40% inthe placebo group.

Acute Pain Assessment

The median times to loss of acute phase pain were 20, 21, and 22 daysfor the famciclovir 500 mg, famciclovir 750 mg, and placebo groups,respectively. Hazard ratios were 1.2 for the famciclovir 500 mg groupand 1.1 for the famciclovir 750 mg group. Although there were nostatistically significant differences between the treatment groups inthe intention-to-treat population, in the efficacy-evaluable population,patients receiving famciclovir 500 mg lost pain significantly fasterthan placebo recipients (p=0.0176).

In addition, patients with severe rash (>50 lesions) at enrollment lostpain faster in both the famciclovir 500 mg (intention-to-treat: hazardratio=1.9; p=0.0028; efficacy-evaluable: hazard ratio=2.9; p=0.0001) andfamciclovir 750 mg (intention-to-treat: hazard ratio =1.3; p=0.2143;efficacy-evaluable: hazard ratio=2.0; p=0.0136) groups. The median daysto loss of pain for the famciclovir 500 mg, famciclovir 750 mg, andplacebo groups were 20, 27, and 30 days, respectively, in theintention-to-treat population and 20, 27, and 53 days, respectively, inthe efficacy-evaluable population. No consistent trends were noted forpatients presenting with mild or moderate rash at enrollment.

Postherpetic Neuralgia Assessment

Although there was a comparable proportion of patients who had painfollowing healing in all treatment groups (52%, 57%, 50% for famciclovir500 mg, famciclovir 750 mg, and placebo, respectively), both of thefamciclovir doses significantly reduced the duration of postherpeticneuralgia in the overall study population (FIG. 1A). Hazard ratios were1.7 and 1.9 for famciclovir 500 mg and 750 mg, respectively, indicatingan almost two-fold reduction in time to postherpetic neuralgiaresolution compared with placebo; the reduction in duration ofpostherpetic neuralgia was statistically significant for both doses offamciclovir (p=0.0202 and 0.0050, respectively). Almost 90% percent ofthe patients analyzed for loss of postherpetic neuralgia had painassessments up to month 5. Median days to loss of postherpetic neuralgiawere 63, 61, and 119 days for the famciclovir 500 mg, famciclovir 750mg, and placebo groups, respectively.

In the subgroup of patients most likely to experience postherpeticneuralgia, ie, those ≧50 years of age, postherpetic neuralgia resolved2.6-times faster in famciclovir recipients than in placebo recipients(p=0.0044 and p=0.0030, for famciclovir 500 mg and 750 mg, respectively;FIG. 1B). Median days to loss of postherpetic neuralgia in these olderpatients were 63, 63, and 163 days for the famciclovir 500 mg,famciclovir 750 mg, and placebo groups, respectively, representing areduction in median time of almost 3.5 months for famciclovirrecipients. Significant benefit was not detected for the subgroup ofpatients <50 years of age.

Safety

Famciclovir was well tolerated, with a safety profile similar to that ofplacebo. The adverse event reported most frequently by the famciclovir500 mg, famciclovir 750 mg, and placebo recipients was headache (23.2%,22.2% and 17.8%, respectively) followed by nausea (12.3%, 12.6%, and11.6%, respectively). For events indicated by the investigator asrelated to study medication (related, possibly related, unknown or whereassessment was missing), once again, the most common adverse events inthe famciclovir 500 mg, famciclovir 750 mg and placebo groups wereheadache (8.0%, 8.1%, and 6.8%, respectively) and nausea (5.1%, 3.0%,and 8.2%, respectively). Famciclovir was not associated withabnormalities in hematology, liver function, clinical chemistry, orurinalysis parameters.

Discussion

Famciclovir given three times daily for seven days demonstratedsignificant reductions in the acute signs and symptoms of herpes zosterand the duration of viral shedding. Most striking was that the time tocessation of postherpetic neuralgia was significantly reduced inpatients who received famciclovir. Famciclovir was well tolerated, withan adverse event incidence comparable with that of placebo. No doseresponse relationship in efficacy or safety was apparent between the twofamciclovir doses.

For many years, acyclovir given 800 mg five times daily for seven to tendays has been the only oral antiviral agent approved for treatment ofacute herpes zoster. Its effectiveness in lessening the acute signs andsymptoms of herpes zoster has been established (6, 7, 21-23), but "theeffects of acyclovir on postherpetic neuralgia are less clear cut." (10)

Postherpetic neuralgia is a common severe complication of herpes zoster.In the largest acyclovir zoster trial (McKendrick et al 8!), nodifference was shown between acyclovir and placebo in either theincidence or the duration of postherpetic neuralgia, despite enrollingonly those patients most at risk of developing postherpetic neuralgia(eg, elderly). However, in two smaller trials (Huff et al 7!; Morton andThompson 24!) which enrolled both young and elderly patients in aboutequal proportions, some effects were seen during the first three months,but not during months 4 to 6. When one of these studies was re-analyzed(Huff et al 9!), a significant effect was seen on all zoster-associatedpain (ie, continuum of pain from enrollment into study until completecessation), but postherpetic neuralgia was not addressed.

Additionally, a recent study evaluating acyclovir administered for 7 or21 days with or without concomitant prednisolone for the treatment ofacute herpes zoster revealed that although acute pain was reduced inpatients treated with concomitant prednisolone or 21 days of acyclovircompared with those who had received 7 days of acyclovir treatmentalone, neither the frequency of zoster-associated pain nor the time tocomplete cessation of pain was affected by the 14 additional days ofacyclovir treatment or by concomitant prednisolone therapy (10). Noinformation on the duration of postherpetic neuralgia was reported fromthat study. Also, as this study did not include a placebo control, noconclusion can be drawn regarding the effect of acyclovir onpostherpetic neuralgia.

Postherpetic neuralgia has been defined in relationship to acute zosteronset (6-8, 24), at time points ranging from one to six months afterzoster rash appears, and in relationship to healing of zoster lesions(25, 26), as was done in the current study. Since the definition ofpostherpetic neuralgia varies between studies, comparability of patientpopulations may be shown by examining the prevalence of pain in theplacebo-treated groups persisting six months after zoster rash onset. Inthe current study, 18.5% of the placebo recipients reported pain sixmonths after rash onset; this value is in agreement with the prevalenceof pain reported by placebo recipients in other published studies (6, 8,24).

In this study, famciclovir clearly demonstrated a significant reductionin the duration of postherpetic neuralgia in comparison with placebo.Important features of the current study include prospectively definedpostherpetic neuralgia, the duration of follow-up (almost 90% ofpatients in the postherpetic neuralgia analysis were assessed fivemonths after healing), and reliance on rigorous statistical methodologyto evaluate the duration of postherpetic neuralgia. The present reportsummarizes postherpetic neuralgia over the entire follow-up period (fivemonths after healing) in a single statistic (ie, the hazard ratio).Additionally, the loss of pain was identified as the time at which thepatients reported no zoster related pain and, most importantly, theywere continued in the study and never reported pain again for theremainder of the study period. Thus, the value of two for an estimatedhazard ratio, indicates that the event of interest occurs twice asrapidly in patients receiving famciclovir than in controls. Patientsreceiving famciclovir during acute zoster lost postherpetic neuralgiaalmost two times faster than those receiving placebo (500 mg: hazardratio=1.7, p=0.0202; 750 mg: hazard ratio=1.9, p=0.0050). In olderpatients (L≧50 years of age), who are more at risk and in whompostherpetic neuralgia persists longer, those who were treated withfamciclovir during acute zoster lost pain 2.6-times faster than thosewho received placebo (500 mg: p=0.0044; 750 mg: p=0.0030), resulting ina 3.5-month reduction in median duration of postherpetic neuralgia.

In conclusion, oral famciclovir 500 mg or 750 mg administered threetimes daily for seven days during acute zoster offers significantbenefit to patients with herpes zoster by providing a well toleratedconvenient dosage regimen, effective relief of acute zoster signs andsymptoms, and shortening the duration of postherpetic neuralgia.

The Collaborative Famciclovir Herpes Zoster Study Group

Baylor College of Medicine, Houston, Tex.: Suzanne Bruce, MD, AnnetteHarris, MD, Anne Epstein, MD, Lisa Lowry, MD, Howard Rubin, MD, JohnDupuy, MD, Jay Hendricks, MD, Jeanette Greer, MD; Beverly Hills, Calif.:Marvin Rapaport, MD; Bucks County Clinical Research, Morrisville, Pa.:David J Miller, DO, Brad S Friedmann, DO, Randi M Silverbrook, DO, WayneMarley, MD; Clinical Study Center, Fort Myers, Fla./ Cape Coral, Fla:Stephen R Zellner, MD, David D Michie, PhD, Felix Mestas, MD, RonicaKluge, MD, Quinnon R Purvis, MD, Nancy Schleider, MD, Juan Domingo, MD;Colorado Medical Research Center, Denver, Colo.: James M Swinehart, MD,Kathy Williams, RN, Lisa Shultz, RN, Bonnie Rochambeaum LPN; DeaconessFamily Medicine/Old Orchard Geriatrics & Family Medicine/SouthsideFamily Practice/Spurgeon Medical Group/St. Louis Medical Research, St.Louis, Mo.: James Nahlik, MD, Rick A Barbarash, PharmD, David Campbell,MD, James Price, MD, Mark King, MD, Percival Moraleda, MD, Michael Toro,MD, Marta Mortensen, MD, Melinda Walker, MD, Bryan Steele, MD, KathleenCastellanos, MD, M Dale Terrel, MD, Jessee Crane, MD; Robert Zink, MD,Scott Soerries, MD, Charles Nester, MD, Stephen Nester, MD, Glennon Fox,MD, Charles Crecelius, MD, Morton Singer, MD, Linda Stanton, MD; GeorgeWashington University Medical Center, Washington, D.C.: Mervyn L Elgart,MD, Gayle Masri-Fridling, MD, Michael Noonan, MD, Pamela Scheinman, MD,M Carol McNeely, MD, Maria Turner, MD; Georgetown University MedicalCenter, Washington, D.C.: Virginia I Sulica, MD; Georgia ClinicalResearch Center, Atlanta, Ga.: Stephen J Kraus, MD, Edmond I Griffin,MD, D Scott Karempelis, MD, Bette C Potter, MD, Diane M Smith, LPN;Harborview Medical Center, Seattle, Wash.: Lawrence Corey, MD, ThomasGill, MD; Henry Ford Hospital, Detroit, Mich.: Orlando G Rodman, MD,Robert Norum, MD, Dennis Babel, PhD; Le Centre Hosptitalier del'Universite Laval, Ste. Foy, Quebec, Canada: Alain Martel, MD; LSUSchool of Medicine/Charity Hospital of Louisiana at New Orleans/LSULions Clinic, New Orleans, La.: Lee T Nesbitt, Jr. MD, Brian D Lee, MD,Donna G Heitler, MD, Eric Hollabaugh, MD; Maplewood FamilyPractice/Piedmont Research Associates, Winston-Salem, N.C.: John BRThomas, MD, Sherrill D Braswell, Jr., MD, John G Roach III, MD, RichardC Worf, MD, Champ M Jones, MD, Thomas B Cannon, MD, Thomas W Littlejohn,III, MD, Keith V VanZandt, MD, Gina Gottesman Shar, MS; Melbourne,Australia: Andrew Hellyar, MBBS; Minnesota Clinical Study Center,Fridley, Minn.: H Irving Katz, MD, Steven E Prawer, MD, Jane S Lindholm,MD, Ngo T Hien, MD, Frederick S Fish, MD, Jack C Scott, MD, StevenKempers, MD, M Elizabeth Briden, MD; Montreal, Quebec, Canada: MichelLassonde, MD, Claude Girard, MD; Montreal, Quebec, Canada: Victor Oliel,MD; Mt. Sinai Hospital, Toronto, Ontario, Canada: Andrew Simor MD, DLow, MD, H Velland, MD, W Gold, MD; Nalle Clinic/Metrolina/Nalle Clinic,Charlotte, N.C.: John L Benedum, MD, Ophelia E Garmon-Brown, MD, WSTucker, Jr., MD, Kim Tam, MD, Ed Landis, MD, C. Whit Blount, MD, SelwynSpangenthal, MD, Geoffrey Chapman, MD; Palm Beach Center for ClinicalInvestigation, W Palm Beach, Fla.: Lee Fischer, MD, Holly W. Hadley, MD;St. Joseph's Health Centre of London, London, Ontario, Canada: DanielGregson, MD, Ole Hammerberg, MD; St. Michael's Hospital Toronto,Ontario, Canada: Ignatius Fong, MD; SIU School of Medicine, MemorialMedical Center, St. John's Hospital, Springfield, Ill.: Larry A VonBehren, MD, Sergio Rabinovich, MD, Nancy Khardori, MD; SmithKlineBeecham Pharmaceuticals, Philadelphia, Pa., USA, Brentford, Middlesex,UK, Melbourne, Australia, and Oakville, Ontario, Canada: Robin Saltzman,MD, Ron Boon, B.Sc.(Hons)., C.Biol., M.l.Biol., David Fitts, PhD,Charles Grier, PhD, David Griffin, Duncan McKay, Richard Birkenmaier,Simon Bishop, G. Lynn Marks, MD, Leslie Locke, PhD, Regina Jurewicz,RPh, Susan Weill, BSN, Thomas Mayewski, Carol Frazier, Ann Grossman,James MacDonald, Pam Murphy, Kathryn Stiede, Mary Beth Weigart, MaryLevidiotis, Marilyn Hosang, Jim Parsons; Sunnybrook Medical Centre,Toronto, Ontario, Canada: Anita R. Rachlis, MD; Toronto, Ontario,Canada: Gary D Schachter, MD, Ricky K Schachter, MD; University ofAdelaide, Adelaide, South Australia: John Marley, MD, David Gordon, MD,Peter Hallsworth, PhD, Diane Markham, RN, Elizabeth Wilkinson, RN, MGeraldine Smith, RN; University of Arizona Health Sciences Center,Tucson, Ariz.: Kevin Welch, MD; University of California, San DiegoSchool of Medicine/VA Medical Center, San Diego, Calif.: DanielPiacquadio, MD, Ann Fleming, RN; University of Cincinnati, Cincinnati,Ohio: Debra L Breneman, MD, Bhakta V Chetty, MD, Steven Manders, MD,Boris Lushniak, MD; University of Miami, Miami, Fla: Daniel Hogan, MD;University of Newcastle, Callaghan, New South Wales, Australia:Alexander Reid, MD, G Tannock, MD, Nannette Dick, RN, Loma Crossley, RN;University of Texas Medical Branch, Galveston, Tex: Stephen K. Tyring,MD, PhD, Robert Purvis, MD, Dayna Diven, MD, Neill Porter, MD;University of Texas Medical School at Houston, Houston, Tex.: Adelaide AHebert, MD, John Bradford Bowden, MD Keith Edward Schulze, MD;University Hospital, Saskatoon, Saskatchewan, Canada: Kurt E Williams,MD, JM Conly, MD, C Anderson, MD; VA Medical Center, Minneapolis, Minn.:Janellen Smith, MD, Nancy Krywonis, MD; VA Medical Center, Sepulveda,Calif.: Madalene CY Heng, MD; Volunteers In Pharmaceutical Research,Bryan, Tex.: Ted L Rea, MD, Terry Jones, MD; Wenatchee Valley Clinic,Wenatchee, Wash.: Richard Tucker, MD, Byron W Lee, MD, Cooky Ogle;Westlake Village, Calif./ Simi Valley, Calif.: James S Weintraub, MD;Westmead Hospital, Westmead, Australia: A. Cunningham, MBBS, MD, DominicDwyer, MBBS, David Holland, MBBS, Margaret Fordham, RN, Graeme Miller,MBBS, Terina Sylvester, RN; West Paces Ferry Hospital, Atlanta, Ga.:Steven I Marlowe, MD, Mark L Tanner, MD; Wheatridge, Colo.: Pasquale ADiLorenzo, MD.

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2. Portenoy R K, Duma C, Foley K M. Acute herpetic and postherpeticneuralgia: clinical review and current management. Ann Neurol.1986;20:651-64.

3. Loeser J D. Herpes zoster and postherpetic neuralgia. Pain.1986;25:149-64.

4. Strommen G L, Pucino F, Tight R R, Beck C l. Human infection withherpes zoster: Etiology, pathophysiology, diagnosis, clinical course,and treatment. Pharmacotherapy. 1989;8:52-68.

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9. Huff J C, Drucker J L, Clemmer A, Laskin O L, Connor J D, Bryson Y J,et al. Effect of oral acyclovir on pain resolution in herpes zoster: Areanalysis. J Med Virol. 1993;1 (Suppl 1):93-6.

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12. Boyd M R, Bacon T H, Sutton D, Cole M. Antiherpesvirus activity of9-(4-hydroxy-3-hydroxy-methylbut-1-yl) guanine (BRL 39123) in cellculture. Antimicrob Agents Chemother. 1987;31:1238-1242.

13. Boyd M R, Boon R J, Fowles S E, Pagano K, Prince W T, Sutton D, etal. Some biological properties of BRL 42810, a well-absorbed oralprodrug of the anti-herpesvirus agent BRL 39123. Antiviral Res.1988;9:146.

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15. Bacon T, Schinazi R. An overview of the further evaluation ofpenciclovir against herpes simplex virus and varicella-zoster virus incell culture, highlighting contrasts with acyclovir. Antiviral ChemChemother. 1993;4(Suppl):25-36.

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18. Standring-Cox R, Bacon T H, Howard B, Gilbart J, Boyd M R. Prolongedactivity of penciclovir against varicella-zoster virus in cell cultureAbstract!. In: Program and Abstracts of the 7th International Conferenceon Antiviral Research. Charleston, S.C.; 1994:114.

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                  TABLE 1    ______________________________________    Patient Characteristics at Study Enrollment                 Famciclovir                 500 mg    Famciclovir 750 mg                                        Placebo    ______________________________________    No. of Patients                 138       135          146    % Female/Male                 45.7/54.3 48.9/51.1    47.3/52.7    Mean Age (years)                 50.1      49.5         49.1    <50 years (%)                 49.3      48.9         52.1    ≧50 years (%)                 50.7      51.1         47.9    Duration of Rash (%)    <48 hours    47.8      56.3         49.3    48-72 hours  51.5*     43.7         50.7    Location of Rash (%)    Thoracic     50.0      56.3         54.8    Cervical     25.4      18.5         26.0    Lumbar       14.5      13.3         13.7    Cranial      5.1       7.4          4.1    Sacral       5.1       4.4          1.4    Severity of Rash (%)    No lesions   --        --           0.7    Mild         21.0      25.9         23.3    Moderate     22.5      20.7         24.7    Severe       56.5      53.3         51.4    Severity of Pain (%)    None         5.8       5.9          8.2    Mild         24.1      28.9         33.6    Moderate     36.5      34.1         30.8    Severe       32.8      31.1         27.4    ______________________________________     *One patient (0.7%) enrolled at 77 hours after rash onset.

                  TABLE 2    ______________________________________    Cutaneous Lesion Resolution*              Famciclovir                        Famciclovir              500 mg    750 mg      Placebo    ______________________________________    Time to Full Crusting    N           119 (91)    120 (92)    133 (101)    Median  days!                5 (6)       6 (8)       7 (7)    Hazard ratio                1.3 (1.5)   1.4 (1.5)    95% C.I.    1.0-1.7 (1.1-2.0)                            1.0-1.9 (1.1-2.1)    p value.sup.†                0.0995 (0.00245)                            0.0228 (0.0162)    Time to Loss of    Vesicles    N           133 (104)   131 (103)   143 (110)    Median  days!                5 (5)       5 (5)       6 (6)    Hazard ratio                1.4 (1.6)   1.7 (2.0)    95% C.I.    1.1-1.9 (1.2-2.2)                            1.3-2.2 (1.4-2.7)    p value.sup.†                0.0129 (0.0024)                            0.0004 (0.0001)    Time to Loss of Ulcers    N           72 (55)     73 (59)     89 (70)    Median  days!                7 (7)       7 (7)       9 (10)    Hazard ratio                1.6 (1.7)   1.6 (1.7)    95% C.I.    1.1-2.2 (1.2-2.5)                            1.1-2.2 (1.2-2.5)    p value.sup.†                0.0119 (0.0064)                            0.0087 (0.0065)    Time to Loss of Crusts    N           129 (103)   126(101)    142 (112)    Median  days!                19 (19)     20 (20)     21 (21)    Hazard ratio                1.3 (1.5)   1.2 (1.2)    95% C.I.    1.0-1.7 (1.1-2.0)                            0.9-1.6 (0.9-1.6)    p value.sup.†                0.0476.sup.‡  (0.0092)                            0.1926 (0.2185)    ______________________________________     *Analyses for the intentionto-treat and efficacyevaluable (displayed in     parentheses) populations     .sup.† Famciclovir dose compared with placebo     .sup.‡ Not statistically significant after adjusting for     multiple comparisons (20)

We claim:
 1. A method for the treatment of PHN in mammals, which methodcomprises administrating to the mammal in need of such treatment, aneffective amount of famciclovir or penciclovir, or a pharmaceuticallyacceptable salt thereof.
 2. A method according to claim 1 wherein thetreatment is within 72 hours of rash onset.
 3. A method according toclaim 2 wherein the treatment is within 48 hours of rash onset.
 4. Amethod according to claim 1 where the treatment period is 7 days.
 5. Amethod according to claim 1 wherein the treatment is carried out onpatients of greater than 50 years of age.
 6. A method according to claim5 wherein the treatment is carried out on patients of greater than 60years of age.
 7. A method according to claim 6 wherein the treatment iscarried out on patients of greater than 70 years of age.
 8. A methodaccording to claim 1 wherein the compound is famciclovir.
 9. A methodaccording to claim 8 wherein famciclovir is administered at a dose of250 mg, 500 mg or 750 mg, once, twice or three times a day.
 10. A methodaccording to claim 9 wherein famciclovir is administered at a dose of250 mg three times a day.
 11. A method according to claim 9 whereinfamciclovir is administered at a dose of 500 mg three times a day.
 12. Amethod according to claim 9 wherein famciclovir is administered at adose of 500 mg twice a day.
 13. A method according to claim 9 whereinfamciclovir is administered at a dose of 750 mg once a day.
 14. A methodaccording to claim 1 wherein the mammal is a human.
 15. A method for theprophylactic treatment of PHN in a human in need of such treatment,which method comprises administrating to said human, an effectiveprophylactic amount of famciclovir or penciclovir, or a pharmaceuticallyacceptable salt thereof.
 16. A method according to claim 15 wherein thecompound is famciclovir.
 17. A method according to claim 16 whereinfamciclovir is administered at a dose of 250 mg, 500 mg or 750 mg, once,twice or three times a day.
 18. A method according to claim 17 whereinfamciclovir is administered at a dose of 250 mg three times a day.
 19. Amethod according to claim 15 wherein the treatment is carried out onpatients of greater than 50 years of age.
 20. A method according toclaim 19 wherein the treatment is carried out on patients of greaterthan 60 years of age.
 21. A method according to claim 20 wherein thetreatment is carried out on patients of greater than 70 years of age.